New progress has been made in enantiomeric selective parallel kinetic splitting

Recently, the research group of Zhu Qiang/Luo Shuang of the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, used the strategy of parallel kinetic disintegration to synthesize two heterocyclic compounds containing quaternary carbon chiral centers with two different skeleton types through palladium-catalyzed enantiomeric selective cyclimidation reaction. Related research results include “Parallel Kinetic Resolution through Palladium-Catalyzed Enantioselective Cycloimidoylation: En Route to Divergent N-Heterocycles Bearing a Quaternary Stereogenic Center” The title was published in ACS Catal.

The most common way to obtain a single enantiomer of chiral compounds is asymmetric catalytic conversion of achiral substrates, enantioselectively generating chiral factors. Another major approach is to convert racemate mixtures that already contain chiral factors into a single enantiomer product. This approach can be achieved through three strategies: kinetic splitting (KR); Dynamic Dynamics Splitting (DKR); and parallel kinetic splitting (PKR). KR is the use of two enantiomer substrates converted to different rates (k1 >> k2 or k2 >> k1) under the same asymmetric catalytic conditions, ideally 50% of the substrate of one configuration is completely converted to a single configuration of the product, while 50% of the substrate of the other configuration is completely unresponsive and can be recovered. In fact, as the reaction progresses, the relative concentration of reaction substrates in the “inferior” configuration increases, and it also participates in the reaction, resulting in the formation of products in the “harmful” configuration, thereby reducing the enantioselectivity of the product. The DKR strategy effectively overcomes the disadvantage of KR, that is, the continuously enriched “disadvantage” configuration reaction substrate can be continuously racemized, partially converted into “advantageous” substrate, and then continuously generate the product of the target configuration. Ideally, racemate substrates can be converted 100% to a single configuration product by DKR, but only if the substrates of the two configurations can be rapidly interchanged under reaction conditions (k1 >> k2 and k3 >> k2). To overcome the inherent limitations of KR and DKR, Vedejs and Chen introduced another strategy called parallel kinetic disintegration (PKR) in 1997, in which two enantiomeric substrates are converted at the same or close rate (k1≈k3 and k1>> k4 and k3>>k2) along two different reaction pathways, yielding two products of a single enantiomer. Under the condition of an asymmetric reaction, it is a great challenge to achieve both chemoselectivity and enantioselective regulation, that is, the regulation of four reaction routes of two substrates and two products. Another challenge with PKR strategies is that the resulting two products are generally structurally similar, making product separation very difficult, so practical PKR reactions are rare (Figure 1).

Figure 1. Dynamic splitting, dynamic dynamics splitting, and parallel dynamics splitting

Although there have been some examples of successful PKR, there are few reports of products with different structures and separation by column chromatography. In 2003, Fu reported a novel rhodium-catalyzed C-H activation of aldehydes on the alkyne chain, followed by cyclization with alkynes, to synthesize cyclobutanone and cyclopentenone with a limited range of substrates with good yield and enantioselectivity. Tanaka et al. used similar substrates and isocyanates to intermolecular occurrence[4+2]Cycloaddition yields enantioselective derivatives of heptamide and cyclopentenone. In 2017, Cramer synthesized two unique nitrogen heterocyclic skeletons, 3-azabicyclic by PKR reaction[3.1.0]Hexane and 1H-isoindole with quaternally stereogenerated centers. However, in these reactions, the scope of application of the substrate is relatively narrow. In addition, heterocycles containing quaternary carbon stereocenters are widely present in natural products, drugs, and pesticides, however, enantioselective synthesis of them is a challenging task (Figure 2).

Figure 2. Enantiomeric selective PKR constructs the backbone of different rings

Based on the previous work, Zhu Qiang/Luo Shuang’s research group developed the first palladium-catalyzed enantioselective C(sp2)-H imideation parallel kinetic splitting reaction. The racemic isonitrile was studied as the starting material, and dihydroisoquinoline and 1H isoindole with quaternary carbon stereocenter were generated. The reaction can tolerate many types of substrates and can proceed smoothly under mild conditions. The five-membered and six-membered rings constructed from this PKR strategy can be easily separated by column chromatography, which makes this parallel kinetic separation very practical. The authors also performed DFT calculations to explore the reaction mechanism and sources of enantioselectivity (Figure 3).

Figure 3. Palladium-catalyzed Enantioselective C(sp2)-Himylimylation Energy Distribution (Simplified Version)

The first author of the paper is doctoral student Wang Xilong, and the corresponding authors are researcher Zhu Qiang and associate researcher Luo Shuang. The research was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province and other projects. (Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences)

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